CDS T cell responses are remarkably diverse and play vital roles in immune mediated viral control. Thus, there is a crucial need to decipher the developmental cues that drive the differentiation of phenotypically and functionally distinct CDS T cell subsets, define how these constituents cooperate to achieve infection control, and delineate the signals that help sustain these populations over time. Our proposal is based upon a series of recently published and preliminary findings that have advanced our understanding of the importance of intercellular adhesion molecule (ICAM)-I in determining the composition and properties of anti-viral CDS T cell responses. The experimental plan is designed to capitalize on these observations and generate novel fundamental insights into how and when ICAM-1 interactions configure the memory CDS T cell pool, and program protective efficacy. In addition, we will also determine whether tactically targeting ICAM-1 interactions improves immunity and viral control. Promisingly, we have shown that mitigating ICAM-1 interactions preserves anti-viral CDS T cells which usually succumb to exhaustion during chronic viral infections. Thus, our studies have the potential to impact the field by providing new fundamental information regarding how CDS T cell responses are regulated, as well as deliver proof of principle evidence that blocking ICAM-1 interactions is a viable strategy for augmenting immunity to acute, chronic, and bystander infections. This is especially significant as practical strategies to enhance responses by manipulating the anti-viral CDS T cell pool are limited. We also propose to integrate our ICAM-1 studies, showing the retention of effector-phenotype CDS T cells following infection, with our new discovery that IL-21 helps to maintain effector-memory CDS T cells. Given the ubiquitous roles of CDS T cells in anti-viral defense our studies may broadly impact the field by defining the principles that govern and configure the development of these responses. Significantly, they will decipher how ICAM-1 interactions skew the composition of the antiviral CDS T cell pool and whether this can be targeted to enhance immunity.